Background and Aims To elucidate the genetic architecture of blood pressure (BP) and heart rate (HR) during early life and assess their potential relevance to adult health outcomes.Methods The largest genome-wide association study (GWAS) meta-analyses to date of childhood systolic BP, diastolic BP, pulse pressure, and mean arterial pressure (n = 28 425) and HR (n = 22 565) were conducted in children of European ancestry aged 4-17 years. Follow-up analyses included comparisons with adult GWAS results, polygenic risk score (PRS) analyses in independent cohorts of diverse ancestries, and a phenome-wide association study in the UK Biobank.Results Eight genome-wide significant loci were identified for childhood BP (KIAA2013, CACNB2, PLCE1, PAX2, COL4A2, RP11-236L14.1, CFDP1, TPX2) and three loci for childhood HR (CCDC141, ACHE, MYH6); all novel in children but previously reported in adults. Childhood PRSs explained up to 1.6% of BP variance and 5.2% of HR variance among children of European ancestry. Genetic correlations between childhood and adulthood BP traits were moderate (rg = 0.4-0.7), suggesting age-specific genetic effects on BP. In the UK Biobank, higher childhood BP PRS levels were significantly associated with a broad range of adult health outcomes, particularly cardiometabolic outcomes such as hypertension, angina, myocardial infarction, and cardiovascular disease-related mortality.Conclusions These findings advance the understanding of the genetic architecture of childhood BP and HR and provide compelling genetic evidence linking childhood BP to a broad spectrum of adult health outcomes-particularly cardiometabolic conditions-which may inform targeted prevention strategies from a young age.

Sophie Visvikis-Siest*, Maria G. Stathopoulou, Raute Sunder-Plassmann, Behrooz Z. Alizadeh, Robert Barouki, Ekaterina Chatzaki67, Georges Dagher891011†, George Dedoussis, Panagiotis Deloukas, Alexander Haliassos, Brigitte Boisson Hiegel, Vangelis Manolopoulos615, Christine Masson, Guillaume Paré, Markus Paulmichl, Alexandros M. Petrelis118, Csilla Sipeky, Belgin Süsleyici, Georges Weryha, Alex Chenchik, Paul Diehl, Robin E. Everts, Alexander Haushofer, John Lamont, Ruth Mercado, Heiko Meyer, Herna Munoz-Galeano, Helena Murray, Ferrier Nhat, Charity Nofziger, Wolfgang Schnitzel and Stavroula Kanoni*

Background and purpose: Patients with type 2 diabetes mellitus (T2DM) are prone to developing diabetic peripheral neuropathy (DPN) with an increased risk of injuries while walking, potentially leading to plantar ulcers. We aimed to assess the early gait changes in T2DM patients without clinical signs of DPN in comparison to age-matched healthy controls (HC). Subjects and Methods: One hundred T2DM patients (78 women, mean age: 66.4 ± 11.5 years) and 50 age-matched HC (34 women, mean age 62.1 ± 7.9 years) were evaluated with the PODOSmart® gait analysis device. Anthropometric and biochemical data, as well as dietary habits were collected for all participants. T2DM patients also completed the Diabetes Distress (DS) self-report validated questionnaire. Results: One patient was excluded from the study due to lack of recent biochemical data. Among the T2DM patients, 88.9% reported little or no DS and 11.1% moderate DS. The T2DM group had higher body mass index, waist circumference, systolic blood pressure, glycated hemoglobin A1c, sodium, white blood cell count, triglycerides and low-density lipoprotein cholesterol, but lower high-density lipoprotein cholesterol than HC (p < 0.05 for all comparisons). The MedDiet score was satisfactory in both groups (p > 0.05). Significant differences were found between the two study groups in gaitline heel off, propulsion speed, foot progression angle, time taligrade phase, stride length, walking speed, angle attack, oscillation speed, pronation-supination toe off and clearance. Conclusions: The T2DM patients without self-reported DS or clinical signs of DPN may exhibit significant differences in several gait parameters analyzed with PODOSmart®. Whether gait analysis can be used as an early diagnostic tool of T2DM complications should be further explored.

The Apolipoprotein E (APOE) genotype has been shown to be the strongest genetic risk factor for Alzheimer's disease (AD). Moreover, both the lipolysis-stimulated lipoprotein receptor (LSR) and the vascular endothelial growth factor A (VEGF-A) are involved in the development of AD. The aim of the study was to develop a prediction model for AD including single nucleotide polymorphisms (SNP) of APOE, LSR and VEGF-A-related variants. The population consisted of 323 individuals (143 AD cases and 180 controls). Genotyping was performed for: the APOE common polymorphism (rs429358 and rs7412), two LSR variants (rs34259399 and rs916147) and 10 VEGF-A-related SNPs (rs6921438, rs7043199, rs6993770, rs2375981, rs34528081, rs4782371, rs2639990, rs10761741, rs114694170, rs1740073), previously identified as genetic determinants of VEGF-A levels in GWAS studies. The prediction model included direct and epistatic interaction effects, age and sex and was developed using the elastic net machine learning methodology. An optimal model including the direct effect of the APOE e4 allele, age and eight epistatic interactions between APOE and LSR, APOE and VEGF-A-related variants was developed with an accuracy of 72%. Two epistatic interactions (rs7043199*rs6993770 and rs2375981*rs34528081) were the strongest protective factors against AD together with the absence of ε4 APOE allele. Based on pathway analysis, the involved variants and related genes are implicated in neurological diseases. In conclusion, this study demonstrated links between APOE, LSR and VEGF-A-related variants and the development of AD and proposed a model of nine genetic variants which appears to strongly influence the risk for AD.

À notre connaissance peu d’études ont évalué l’épaississement échographique de l’espace intima-média (EIM) veineux. L’EIM est selon certains auteurs un marqueur indirect de la maladie veineuse chronique (MVC). L’objectif de l’étude est d’évaluer par échographie Doppler (ED) l’EIM veineux chez des patients atteints de MVC sur trois tranches d’âge. Mesure prospective de l’EIM par un échographe Toschiba Aplio 300, Sonde haute fréquence, (7–15 Hz), chez 31 patients atteints de MVC, d’âge moyen de 53,54 ans. Ils ont été divisés en trois groupes d’âge successifs afin de comparer la relation EIM et âge entre les groupes. Les mesures ont été faites sur une veine singulière, la veine accessoire postérieure de jambe (VAPJ) chez des patients atteints de MVC. Nous n’avons pas trouvé de corrélation entre âge et EIM dans les trois groupes d’âge selon le Kruskal test (p-value = 0,624). Des études ont montré une augmentation de la fibrose et de l’épaississement liés au vieillissement de la valve valvulaire et de la paroi veineuse et une diminution de la compliance de la paroi veineuse. Le fait que l’on n’ait pas retrouvé dans notre étude de lien entre EIM et âge n’est pas synonyme d’absence de modifications sur l’endothélium veineux. Nous savons que bien souvent chez les patients atteints de MVC les modifications peuvent être précoces. Notre étude n’a pas permis de retrouver de lien entre EIM et âge de patients atteints de MVC. La mesure longitudinale d’EIM veineux d’une population, de surcroît comparée à un bras indemne de MVC, pourrait être plus pertinente dans la mesure où les modifications seraient liées principalement au vieillissement. Le développement de nouvelles techniques d’explorations non invasives avec mesure de l’épaisseur de la paroi veineuse et les évaluations morphologiques ouvriraient de nouvelles perspectives en matière de prévention et de traitement.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

The new smart insole PODOSmart®, is introduced as a new tool for gait analysis against high cost laboratory based equipment. PODOSmart® system measures walking profile and gait variables in real life conditions. PODOSmart® insoles consists of wireless sensors, can be fitted into any shoe and offer the ability to measure spatial, temporal, and kinematic gait parameters. The intelligent insoles feature several sensors that detect and capture foot movements and a microprocessor that calculates gait related biomechanical data. Gait analysis results are presented in PODOSmart® platform. This study aims to present the characteristics of this tool and to validate it comparing with a stereophotogrammetry-based system. Validation was performed by gait analysis for eleven healthy individuals on a six-meters walkway using both PODOSmart® and Vicon system. Intraclass correlation coefficients (ICC) were calculated for gait parameters. ICC for the validation ranged from 0.313 to 0.990 in gait parameters. The highest ICC was observed in cadence, circumduction, walking speed, stride length and stride duration. PODOSmart® is a valid tool for gait analysis compared to the gold standard Vicon. As PODOSmart®, is a portable gait analysis tool with an affordable cost it can be a useful novel tool for gait analysis in healthy and pathological population.

Telomere length (TL) is a hallmark of cellular aging and is associated with chronic diseases development. The vascular endothelial growth factor A (VEGF-A), a potent angiogenesis factor, is implicated in the pathophysiology of many chronic diseases. The aim of the present study was to investigate the associations between VEGF-A and TL. TL in leukocytes (LTL) and skeletal muscle (MTL) were measured, 10 VEGF-related polymorphisms genotyped, and VEGF-A plasma concentrations determined in 402 individuals from the TELARTA cohort. LTL/MTL ratio was calculated as an estimate of lifelong TL attrition. Associations between VEGF-A variants and levels, and TL parameters were investigated. We identified one significant association between the minor allele (T) of rs6993770 variant and LTL/MTL ratio (P=0.001143, β=0.0148, SE=0.004516). The rs6993770 is an intronic variant of the ZFPM2 gene, which is involved in haematopoiesis and the identified association with increased telomere attrition could be due to increased haematopoiesis. No significant epistatic interaction was identified, and no association was found between levels of VEGF-A and any of assessed phenotypes. We identified a potential common genetic regulation between VEGF-A and telomere length attrition that could be explained by mechanisms of increased hematopoiesis and production of platelets. VEGF-A and TL could play an important role in personalized medicine of chronic diseases and identification of molecular links between them can promote the understanding of their complex implications.

It is recognized that gait analysis is a powerful tool used to capture human locomotion and quantify the related parameters. PODOSmart® insoles have been designed to provide accurate measurements for gait analysis. PODOSmart® insoles are lightweight, slim and cost-effective. A recent publication presented the characteristics and data concerning the validity of PODOSmart® insoles in gait analysis. In literature, there is still no evidence about the repeatability of PODOSmart® gait analysis system. Such evidence is essential in order to use this device in both research and clinical settings. The aim of the present study was to assess the repeatability of PODOSmart® system. In this context, it was hypothesized that the parameters of gait analysis captured by PODOSmart® would be repeatable. In a sample consisting of 22 healthy male adults, participants performed two walking trials on a six-meter walkway. The ICC values for 28 gait variables provided by PODOSmart® indicated good to excellent test-retest reliability, ranging from 0.802 to 0.997. The present findings confirm that PODOSmart® gait analysis insoles present excellent repeatability in gait analysis parameters. These results offer additional evidence regarding the reliability of this gait analysis tool.

L'ablation thermique endoveineuse est recommandée en première intention sauf dans certaines indications comme les récidives, les ectasies et les veines de gros diamètre. Évaluer l'occlusion de la grande veine saphène (GVS) et comparer son évolution échographique, dans le traitement endoveineux thermique par radiofréquence (RF) et par laser endoveineux (LEV). L'objectif secondaire est d'élargir l'indication de ces deux techniques aux ectasies de la GVS. Étude prospective comparative sur 152 patients ayant bénéficié d'une ablation par RF ou LEV réalisée au bloc opératoire à la clinique St Nabor à Saint-Avold durant l'année 2017 sous anesthésie tumescente écho-guidée contrôlée ciblée (ATEC). L'évolution morphologique des sclérus de la GVS a été comparée après RF ou LEV. Les ectasies veineuses ont été repérées lors de la cartographie initiale. Le critère de jugement était l'aspect échographique du sclérus aux contrôles précoce et tardif, l'absence de recanalisation et de reflux. Le groupe RF comprenait 80 patients (52,6 %) dont 47 femmes (58,8 %). L'âge moyen des patients était de 57,1 ± 13 ans. L'IMC moyen était de 28,9 ± 5,3. Le diamètre moyen de la GVS était de 7,4 mm ± 1,2, il y avait 36 ectasies dont la plus volumineuse était de 14 mm. Le taux d'occlusion était de 98,7 % avec un taux de recanalisation de 1,3 %. Le groupe LEV comprenait 72 patients (47,3 %) dont 45 femmes (62,5 %). L'âge moyen des patients était de 50,5 ± 12,8 ans. L'IMC moyen était de 26,6 ± 5,6 (518,7–39,7). Le diamètre moyen de la GVS était de 7 mm ± 1,4. Il y avait 12 ectasies dont la plus volumineuse était de 12,5 mm. Le taux d'occlusion était de 98,6 % avec un taux de recanalisation de 1,4 %. Ni l'énergie pour le LEV ni le nombre de cycles pour la RF n'est déterminante dans notre étude. Il n'y a pas de différence significative dans l'évolution morphologique du sclérus vers la fibrose rétractile puis la fibrose totale entre les deux procédures mais une évolution plus précoce du sclérus vers la fibrose rétractile a été constatée chez les patients traités par LEV. Nous pensons que le traitement par RF et LEV de la GVS permet d'obtenir une occlusion totale et durable notamment des veineuses ectasiques et de gros calibre sous réserve d'optimiser l'hydro-compression péri-veineuse autour de la source thermique obtenue grâce à la maîtrise de l'ATEC.

Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD). Mendelian randomisation studies, using single nucleotide polymorphisms (SNPs) associated with short LTL, infer a causal role of LTL in ASCVD. Recent results, using the blood-and-muscle model, indicate that higher early life LTL attrition, as estimated by the ratio between LTL and skeletal muscle telomere length (MTL), rather than short LTL at conception, as estimated by MTL, should be responsible of the ASCVD-LTL connection. We combined LTL and MTL measurements and SNPs profiling in 402 individuals to determine if 15 SNPs classically described as associated with short LTL at adult age were rather responsible for higher LTL attrition during early life than for shorter LTL at birth. Two of these SNPs (rs12696304 and rs10936599) were associated with LTL in our cohort (p = 0.027 and p = 0.025, respectively). These SNPs, both located on the TERC gene, were associated with the LTL/MTL ratio (p = 0.007 and p = 0.037, respectively), but not with MTL (p = 0.78 and p = 0.32 respectively). These results suggest that SNPs located on genes coding for telomere maintenance proteins may contribute to a higher LTL attrition during the highly replicative first years of life and have an impact later on the development of ASCVD.

Les troubles de la statique plantaire sont très fréquents chez les patients atteints de maladie veineuse chronique (MVC). Des études anatomiques récentes suggèrent que la pompe veineuse du pied (PVP) est essentiellement localisée dans les veines plantaires latérales (VPL). Il est admis également qu’un mauvais appui podal peut avoir des répercussions sur la posture et la marche du patient. Chaque personne a un profil de marche (PM) unique. Jusqu’à présent, il était difficile d’évaluer et quantifier les paramètres de ce PM en clinique et le lien entre le PM et la MVC n’a pas été étudié. Le Podosmart®, est la première solution d’analyse dynamique du PM adapté à une utilisation en cabinet, et ouvre donc une nouvelle voie de recherche. Explorer la relation entre le PM et la MVC dans le cadre de la consultation en médecine vasculaire. Quinze patients sains et 15 patients suivis pour MVC ont marché en ligne droite sur une vingtaine de mètres avec des semelles connectées. Ce système quantifie 13 paramètres biomécaniques permettant de dresser le PM du patient comme la vitesse de marche (m/s), la cadence de marche (pas/min), la durée de la phase d’appui (s), la durée de la phase oscillante (s), la longueur d’un cycle (m), la vitesse de propulsion du pied au moment du décollage des orteils, la vitesse moyenne de foulée, le nombre de pas, le temps de vol, le temps de contact et les angles de prono-supination. Pour chaque patient, des données cliniques ont été récoltées. Une analyse statistique descriptive a ensuite été appliquée et a été comparée au stade d’insuffisance veineuse selon la classification clinique CEAP. Les principaux résultats de l’analyse factorielle de données mixtes (AFDM) nous ont montré que la CEAP pouvait être corrélée avec la pronation/supination au moment de la pose des orteils (PO) et du décollage du talon (DT). La carte de l’AFMD correspond à plus de 50 % de la variabilité des données. Cette étude utilise une approche complémentaire pour la compréhension de la PVP et de ses caractéristiques. Elle a permis de montrer les premiers éléments de réponse, quant à l’intérêt de l’analyse du PM pour le suivi de la MVC. À terme, nous espérons pouvoir définir un PM spécifique chez les patients atteints de MVC. Pour des tests statistiques et des analyses prédictives plus précis, un échantillon plus important sera nécessaire. L’étude est en cours.

Les études anatomiques récentes suggèrent que la pompe veineuse du pied est essentiellement localisée aux veines plantaires latérales (VPL). Cette affirmation est basée essentiellement sur leur localisation intermusculaire profonde, leur constance et leur diamètre plus grand que les veines plantaires médiales (VPM). Cette étude est une approche morphologique et hémodynamique supplémentaire dans la compréhension de la pompe veineuse plantaire (PVP) et de ses composants.

Telomere length (TL) is a dynamic marker that reflects genetic predispositions together with the environmental conditions of an individual. It is closely related to longevity and a number of pathological conditions. Even though the extent of telomere research in children is limited compared to that of adults, there have been a substantial number of studies providing first insights into child telomere biology and determinants. Recent discoveries revealed evidence that TL is, to a great extent, determined already in childhood and that environmental conditions in adulthood have less impact than first believed. Studies have demonstrated that large inter-individual differences in TL are present among newborns and are determined by diverse factors that influence intrauterine development. The first years of child growth are associated with high cellular turnover, which results in fast shortening of telomeres. The rate of telomere loss becomes stable in early adulthood. In this review article we summarise the existing knowledge on telomere dynamics during the first years of childhood, highlighting the conditions that affect newborn TL. We also warn about the knowledge gaps that should be filled to fully understand the regulation of telomeres, in order to implement them as biomarkers for use in diagnostics or treatment.

[This corrects the article DOI: 10.1371/journal.pone.0220902.].

The 9th traditional biannual conference on Systems Medicine, Personalised Health & Therapy—“The Odyssey from Hope to Practice”, inspired by the Greek mythology, was a call to search for practical solutions in cardio-metabolic diseases and cancer, to resolve and overcome the obstacles in modern medicine by creating more interactions among disciplines, as well as between academic and industrial research, directed towards an effective ‘roadmap’ for personalised health and therapy. The 9th Santorini Conference, under the Presidency of Sofia Siest, the director of the INSERM U1122; IGE-PCV (www.u1122.inserm.fr), University of Lorraine, France, offered a rich and innovative scientific program. It gathered 34 worldwide distinguished speakers, who shared their passion for personalised medicine with 160 attendees in nine specific sessions on the following topics: First day: The Odyssey from hope to practice: Personalised medicine—landmarks and challenges Second day: Diseases to therapeutics—genotype to phenotype an “-OMICS” approach: focus on personalised therapy and precision medicine Third day: Gene-environment interactions and pharmacovigilance: a pharmacogenetics approach for deciphering disease “bench to clinic to reality” Fourth day: Pharmacogenomics to drug discovery: a big data approach and focus on clinical data and clinical practice. In this article we present the topics shared among the participants of the conference and we highlight the key messages.

Sophie Visvikis-Siest*, Alex-Ander Aldasoro Arguinano, Maria Stathopoulou, Ting Xie, Alexandros Petrelis, Georges Weryha, Philippe Froguel, Peter Meier-Abt, Urs A. Meyer, Vid Mlakar, Marc Ansari, Andreas Papassotiropoulos, Georges Dedoussis, Baishen Pan, Roland P. Bühlmann, Mario Noyer-Weidner, Pierre-Yves Dietrich, Ron Van Schaik, Federico Innocenti, Winfried März, Lynn M. Bekris and Panos Deloukas 8th Santorini Conference: Systems medicine and personalized health and therapy, Santorini, Greece, 3–5 October 2016

BACKGROUND Telomere length is associated with a large range of human diseases. Genome-wide association studies (GWAS) have identified genetic variants that are associated with leucocyte telomere length (LTL). However, these studies are limited to adult populations. Nevertheless, childhood is a crucial period for the determination of LTL, and the assessment of age-specific genetic determinants, although neglected, could be of great importance. Our aim was to provide insights and preliminary results on genetic determinants of LTL in children. METHODS Healthy children (n = 322, age range = 6.75-17 years) with available GWAS data (Illumina Human CNV370-Duo array) were included. The LTL was measured using multiplex quantitative real-time polymerase chain reaction. Linear regression models adjusted for age, gender, parental age at child's birth, and body mass index were used to test the associations of LTL with polymorphisms identified in adult GWAS and to perform a discovery-only GWAS. RESULTS The previously GWAS-identified variants in adults were not associated with LTL in our paediatric sample. This lack of association was not due to possible interactions with age or gene × gene interactions. Furthermore, a discovery-only GWAS approach demonstrated six novel variants that reached the level of suggestive association (P ≤ 5 × 10(-5)) and explain a high percentage of children's LTL. CONCLUSIONS The study of genetic determinants of LTL in children may identify novel variants not previously identified in adults. Studies in large-scale children populations are needed for the confirmation of these results, possibly through a childhood consortium that could better handle the methodological challenges of LTL genetic epidemiology field.